Diabetes: Is Inflammation to Blame for Increased Risks?

A Venn diagram depicting the struggles of a person with diabetes could show three overlapping circles: diabetes, chronic diabetes complications, and mental health disorders. The middle, where all three intersect, might be “inflammation.” Two studies published this year explore this intersection and suggest that even small changes in immune biomarkers could be important.

Diabetes, Chronic Complications, and Mental Health

A study by Watanabe et al sought to better understand the relationship between the timing of chronic diabetes complications and mental health in people with diabetes. Using de-identified insurance claims from 2001 to 2018, the team pulled data from more than 44,000 individuals with type 1 diabetes (T1D), 150,000 individuals with type 2 (T2D), and over 300,000 individuals without diabetes (controls). None of the participants had a mental health disorder or a chronic diabetes complication at time of diagnosis or at control matched enrollment date. All groups were matched for age, sex, socioeconomic levels, insurance plan types, education, and their modified Charlson Comorbidity Index.

The chronic complications of diabetes, identified by ICD-9 ad ICD-10 insurance codes, were:

• amputation

• myocardial infarction

• nephropathy/diabetic kidney disease

• neuropathy

• peripheral vascular disease

• retinopathy

• stroke

Mental health disorders were identified using codes for depression and anxiety.

In general, the results demonstrated a bidirectional relationship between chronic diabetes complications and mental health disorders. Looking at all participants, the risk of mental health after a chronic complication emerged was approximately doubled (hazard ratio [HR] 1.9 for 20 to 39 years of age, 2.1 for 40 to 59 years, and 2.9 for ≥60 years; P < 0.05). For participants with a precedent mental health disorder, there is about a 50% increased risk of developing a later chronic complication (HR 1.5 for 20 to 39 years, 1.4 for 40 to 59 years, and 1.6 for ≥60 years; P < 0.05). In other words, when one emerges, the other often follows.

Specific to each group, the team found that patients with T2D and the control group were at greater risk of mental health disorders in general than patients with T1D. Among the controls, having a precedent mental health disorder substantially increased the risk of developing diabetic-like complications compared to the risk observed in participants with diabetes, particularly the participants with T1D.

Study co-author Brian C. Callaghan, MD, a professor of neurology at the University of Michigan, summarized the results in participants without diabetes in this way: “Those without diabetes are much less likely to develop complications. However, compared to someone else without diabetes, having a mental health disorder does increase the risk of complications.”

Lastly, patients with T1D were at greater threat for chronic complications than patients with T2D. Regardless of the type of diabetes, the bidirectional risks between precedent and emergent disorders were similar within the two diabetic groups. In summary, Dr. Callaghan told MedCentral, “A patient with diabetes and a mental health disorder is much more likely to develop complications than a patient with diabetes and no mental health disorder,” and vice versa.

Inflammation as the Intersection

Inflammation has been documented in both T1D and T2D. A related study found that increases in the number of leukocytes and monocytes could increase the risk of developing T2D by 8% and 6% respectively. In T1D, elevations in immune biomarkers, haptoglobin, or leukocyte numbers were documented compared to levels measured in the control group.

Chronic inflammation is also a key player in diabetic complications. Similar changes in immune markers have been recorded in mental health disorders, including genetic overlaps and changes in inflammatory markers, such as C-reactive protein, TNF-α, and several interleukins.

Biomarker Cut-Off Values for Assessing Risks to Mental Health

A second major study examined the changes in immune biomarkers that precede the emergence of psychiatric disorders and established some crucial values that can be helpful in the primary care setting.

The research, led by Zeng et al, used data from the prospective longitudinal Swedish Apolipoprotein-Related Mortality Risk Study (AMORIS), which includes 30 years of follow-up data among 585,279 individuals. During this period, 16% (93,961) were diagnosed with a mental health disorder sometime during follow-up (mean time 24.0 years +/- 9.5 years). The disorders included any psychiatric disorder, depression, anxiety, and/or stress-related disorders.

Several broad themes emerged in the data set. First, mean leukocyte numbers and mean haptoglobin levels were elevated even in samples taken up to 30 years prior to being diagnosed with a mental health disorder. Second, immunoglobulin G (IgG) levels were consistently lower for the 5 to 10 years prior to a psychiatric diagnosis. Third, these differences in immune markers, while statistically significant were not substantially different because the mean values measured for each group were still within normal ranges.

Looking at the data for specific immune biomarkers, collapsed across time, the researchers established cutoff points based on median group values. With few exceptions, those individuals with biomarkers with levels in the upper 50^th percentile were at increased risk of developing a mental health disorder over time (see Table I). Lymphocytes alone were not associated with risks to mental health, however their relationship to other leukocytes altered this risk profile. An increase in the number of neutrophils relative to lymphocytes (neutrophil to lymphocyte ratio: NLR > 1.86) increased the risk by approximately 8% (OR 1.08, 95% CI 1.02-1.13; P <0.05). Increasing the number of lymphocytes relative to monocytes (LMR > 5.5), decreased the risk by about 13% (OR 0.87, 95% CI 0.84-0.91; P < 0.05).

So while Zeng’s study did not look specifically at people with diabetes, another AMORIS partner study found that increased haptoglobin and leukocytes decades earlier were also associated with an increased risk of developing adult-onset T1D (HR; 1.16 and 1.08 respectively).³ As before, the elevated levels of haptoglobin (1.10 g/L) and leukocytes (7.03 x10⁹/L) were not outside the normal range, but would be in the 50^th percentile established in the more recent AMORIS study.⁹